Brain tissue oxygen partial pressure monitoring and prognosis of patients with traumatic brain injury: a meta-analysis

To assess whether monitoring brain tissue oxygen partial pressure (PbtO2) or employing intracranial pressure (ICP)/cerebral perfusion pressure (CCP)-guided management improves patient outcomes, including mortality, hospital length of stay (LOS), mean daily ICP and mean daily CCP during the intensive care unit(ICU)stay. We searched the Web of Science, EMBASE, PubMed, Cochrane Library, and MEDLINE databases until December 12, 2023. Prospective randomized controlled and cohort studies were included. A meta-analysis was performed for the primary outcome measure, mortality, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eleven studies with a total of 37,492 patients were included. The mortality in the group with PbtO2 was 29.0% (odds ratio: 0.73;95% confidence interval [CI]:0.56–0.96; P = 0.03; I = 55%), demonstrating a significant benefit. The overall hospital LOS was longer in the PbtO2 group than that in the ICP/CPP group (mean difference:2.03; 95% CI:1.03–3.02; P<0.0001; I = 39%). The mean daily ICP in the PbtO2 monitoring group was lower than that in the ICP/CPP group (mean difference:-1.93; 95% CI: -3.61 to -0.24; P = 0.03; I = 41%). Moreover, PbtO2 monitoring did not improve the mean daily CPP (mean difference:2.43; 95%CI: -1.39 to 6.25;P = 0.21; I = 56%).Compared with ICP/CPP monitoring, PbtO2 monitoring reduced the mortality and the mean daily ICP in patients with severe traumatic brain injury; however, no significant effect was noted on the mean daily CPP. In contrast, ICP/CPP monitoring alone was associated with a short hospital stay.


Introduction
Traumatic brain injury (TBI) refers to the destruction of the anatomy and physiology of the brain due to external forces.The estimated annual incidence of TBI is 27-69 million Yuqi Shen, Dan Wen and Zhenghua Liang contributed equally to this work.
Mei He hemeimy@163.comSome patients with normal ICP and CPP may still develop cerebral ischemia and hypoxia [10].
Partial pressure of brain tissue oxygen (PbtO 2 ) is a monitoring system for detecting the oxygen tension in the brain.Additionally, PbtO 2 is an indicator that reflects the oxygenation status of the brain by directly measuring the partial pressure of oxygen in the brain using a probe placed within it.The normal range of PbtO 2 is believed to be 16-40mmHg.Furthermore, PbtO 2 of 10-15mmHg indicates mild cerebral hypoxia, and PbtO 2 < 10mmHg indicates severe hypoxia.The purpose of PbtO 2 is to identify episodes of decreased cerebral perfusion with or without associated raised ICP [11] because the partial pressure of oxygen in the brain can change in the early stages of injury [12].Changes may also occur before or independently of increases in ICP [13].PbtO 2 monitoring has been used to assess, judge and regulate brain hypoxia to guide treatment and improve neurological outcomes [14].PbtO 2 can sensitively reflect the blood and oxygen supply to the brain, which is conducive to early detection of cerebral ischemia and hypoxia, and is an independent and sensitive predictor of cerebral ischemia and hypoxia [6].Additionally, PbtO 2 monitoring, ICP < 20mmHg, and CPP > 60mmHg have been reported to alleviate cerebral hypoxia through automatic regulation of the brain simultaneously [8].
However, the results of observational and cohort studies and randomized controlled trials remain controversial.Therefore, this meta-analysis was designed to summarize the effectiveness of this approach.The clinical efficacy and safety of PbtO 2 in patients with TBI were evaluated by comparing the effects of PbtO 2 (or combined) ICP/CPP-guided treatment and ICP/CPP-guided treatment alone on mortality, length of stay, ICP, and CPP during monitoring.

Materials and methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15] were followed in the review process and analyses.The study protocol was registered in PROSPERO (CRD42023494630).

Search strategy
The Web of Science, EMBASE, PubMed, Cochrane Library, MEDLINE databases were searched from inception to December 12, 2023.The search was performed using the following combination of keywords: brain injuries, traumatic or traumatic brain injury or TBI, and brain tissue oxygen or PbtO 2 and monitoring.Search results were restricted to studies with adult participants published in English.

Inclusion and exclusion criteria
We used the following inclusion criteria: type of study (randomized or quasi-randomized controlled trials, cohort studies, or case-control studies); type of participants (studies with patients diagnosed with TBI); type of intervention (comparison of PbtO 2 monitoring alone or combined PbtO 2 and ICP/CPP monitoring with ICP/CPP monitoring alone); and type of outcome (primary outcome: mortality;

Statistical analysis
Statistical analysis was performed using Review Manager 5.4 (RevMan V5.4.1) provided by the Cochrane Collaboration (Oxford, UK).Odds ratios (ORs) with 95% confidence intervals (CIs) were determined to assess pooled effects.Heterogeneity in the included studies was assessed using Q and I 2 tests.A random-effects model was adopted to analyze variations across the included studies.The stability of the results was assessed using sensitivity analysis by eliminating one study at a time.

Study selection
The PRISMA flowchart (Fig.

Study selection and data extraction
We removed duplicate articles from the search results using Endnote (version 9.3).The literature was then screened by two researchers (Yuqi Shen and Dan Wen) according to the inclusion and exclusion criteria outlined above.Disagreements were discussed with a third researcher (Zhenghua Liang) and a consensus was achieved.The extracted data included the first author, publication date, patient care settings, total sample size, intervention measures, and outcome indicators.

Quality evaluation
We assessed the quality of observational cohort studies using the Newcastle-Ottawa Scale (NOS).A score of 0-4 indicated low-quality literature (grade C), while 5-6 indicated medium-quality literature (grade B), and 7-9 indicated high-quality literature (grade A).The quality of randomized Our results demonstrated that the role of PbtO 2 monitoring in reducing mortality remains clear.Four studies included in this meta-analysis reported that PbtO 2 monitoring does not decrease a significant mortality rate.In contrast, seven studies identified a reduction in the risk of mortality.The rate of mortality in the PbtO 2 monitoring group was 29.0% across all studies included in our analysis, which is different from the previously reported rate based on a meta-analysis by Xie [4].Studies have demonstrated that brain hypoxia is associated with poor prognosis after TBI and optimizing PbtO 2 can improve recovery and survival rates [26].Four observational studies [19,20,22,23] and two randomized controlled trials [16,25] included in this meta-analysis demonstrated that when PbtO 2 was incorporated into clinical management decisions, neural function exhibits statistically significant benefits.Additionally, five studies demonstrated that PbtO 2 monitoring increased mortality in patients with TBI.Although no single treatment has been identified to significantly decrease the mortality of these patients in a relatively short period, improving patient outcomes through corresponding interventions is possible.
PbtO 2 monitoring group was associated with prolonged the hospital length of stay; however, it is worth noting that three reports included in this analysis revealed a significant difference in hospital length of stay, while three other studies indicated no such difference between patient groups.However, our meta-analysis results revealed that PbtO 2 monitoring was associated with extended hospital length of stay.Although the severity of TBI at admission was comparable between patient groups, the difference may be attributed to patients in the PtbO 2 monitoring group receiving more intensive life-support treatments, potentially leading to prolonged survival [18].The relationship between PbtO 2 monitoring and extended hospital length of stay in patients with TBI, therefore, needs further evaluation.
Only one study reported a significant relationship between the mean daily ICP and CPP with PbtO 2 monitoring, while four studies reported no significant association.Our meta-analysis suggests that ICP can be reduced further with PbtO2 monitoring.However, mean daily CPP is demonstrated no statistical significance between the PbtO 2 monitoring group and the ICP/CPP group.The discrepancy may stem from differences in the application and assessment methods of brain tissue oxygen monitoring and ICP/ CPP between studies.We suggest that PbtO2 and ICP/CPP monitoring should be standardized, meanwhile, operators require better training to reduce the variations in results.not reporting outcomes of interest (163 articles), case report (46 articles), or meta-analysis or systematic review (43 articles).Eleven articles that met all conditions were identified using full-text screening and included in the final analysis [13,[16][17][18][19][20][21][22][23][24][25].

Study characteristics and quality
The main features extracted from the studies that were included in our analysis are listed in Table 1.We included a total of 37,492 patients, with the sample size ranging from 50 to 35,501 participants per study.On quality assessment, six studies were awarded grade A [13,18,[20][21][22][23], and four were awarded grade B [16,17,19,24,25].Details of the assessment of each study are provided in Tables 2 and 3.

Primary outcome: mortality
The mortality rate was 29.0% in 2026 patients with TBI in the PbtO 2 monitoring group.The OR for mortality in the PbtO 2 monitoring group, compared to that of ICP/CPP, was 0.73 (95% CI: 0.56-0.96;P = 0.03; I 2 = 55%), thus demonstrating a significant benefit (Fig. 2).

Secondary outcomes
The mean difference(MD)in the length of hospital stay in patients in the PbtO 2 monitoring group (reported in six studies) was 2.03 (95% CI: 1.03-3.02;P<0.0001;I 2 = 39%);therefore the overall length of stay in the hospital in the ICP/CPP monitoring group was shorter than that in the PbtO 2 monitoring group (Fig. 3).
The MD in the mean daily ICP between PbtO 2 monitoring group and ICP/CPP monitoring group was − 1.93 (95%CI: -3.61 to -0.24; P = 0.03; I 2 = 41%)(based on five studies).The mean daily ICP in the PbtO 2 monitoring group was lower than that in the ICP/CPP monitoring group (Fig. 4).
The MD in the mean daily CPP between the PbtO 2 monitoring group and ICP/CPP monitoring group was 2.43 (95%CI: -1.39 to 6.25; P = 0.21; I 2 = 56%), thus demonstrating a non-significant benefit(based on five studies).PbtO 2 monitoring did not improve the mean daily CPP (Fig. 5).

Discussion
We pooled the results of nine retrospective cohort studies and two randomized controlled trials involving 37,492 patients with TBI, including 2,096 in the PbtO 2 monitoring group and 35,396 in the ICP/CPP monitoring group.Our primary meta-analysis investigated the impact of brain studies.However, high-quality randomized controlled trials can address these limitations.

Conclusions
In this systematic review and meta-analysis of 11 carefully selected studies, we compared PbtO 2 monitoring with ICP/ CPP monitoring in patients with TBI.Our analysis revealed that PbtO 2 monitoring can decrease mortality and ICP but has no significant effect on and CPP.ICP/CPP monitoring appears to be associated with a short hospital length of stay, however, and we recommend this approach for patients with

Limitations
This study has some limitations.First, this study included two randomized controlled trials, while the remaining studies were retrospective cohort studies.Cohort studies have a greater risk of bias than randomized controlled trials.Second, since these retrospective studies were not randomized, the characteristics of patients included in the two evaluated groups may have varied.Additionally, different operators on the application of tissue oxygen monitoring is also diverse.Third, some studies selected a historical cohort as a control, which may have affected the comparability between

Fig. 3 Fig. 2 Fig. 4
Fig. 3 Forest plot the effects of PbtO2 monitoring towards overall LOS

Table 1
Characteristics and quality of included studies Bcontrolled trials was assessed using the Cochrane Risk of Bias Tool.A study was awarded grade A if the standards were completely met, grade B if the standards were partially satisfied, and grade C if none of the standards were met.
1) displays that 1862 articles were originally retrieved; 996 were retained after removing duplicates.During the first screening of titles and abstracts, 935 articles were excluded for the following reasons: irrelevant topic (538 articles), irrelevant population (145 articles), secondary outcomes: length of stay in hospital, mean daily ICP, and mean daily CPP).Studies were excluded if they were published in languages other than English or as conference abstracts, case reports, or letters.Studies that included children; studies without sufficient data; and studies that reported data incorrectly (not appropriate for synthesis) were also excluded.

Table 2
Quality and risk of bias assessment using the Newcastle-Ottawa Scale (NOS) for observational studies

Table 3
Quality of evidence (GRADE) and of the risk of bias assessment by using the Cochrane ROB tool 2 for randomized clinical trials